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Deuterated tetrapeptides that target mitochondria

a technology of mitochondria and deuterated tetrapeptides, which is applied in the direction of peptides, drug compositions, peptides/protein ingredients, etc., can solve the problems of poor absorption, distribution, metabolism and/or excretion (adme) properties, and many current medicines suffer

Inactive Publication Date: 2020-11-19
STEALTH BIOTHERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides deuterated analogs of SBT-20 and elamipretide (MTP-131). These analogs have improved solubility and may have improved efficacy in treating ischaemia-reperfusion injury and myocardial infarction. The compounds have been shown to have protective effects in animal models. The invention also provides pharmaceutical compositions containing the compounds and methods of treating or preventing the diseases using the compounds.

Problems solved by technology

Many current medicines suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties that prevent their wider use or limit their use in certain indications.
Poor ADME properties are also a major reason for the failure of many drug candidates in clinical trials.
While formulation technologies and prodrug strategies can be employed in some cases to improve or alter certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates.
One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body.
This approach, however, introduces a number of potential treatment problems, such as poor patient compliance with the dosing regimen, side effects that become more acute with higher doses, and increased cost of treatment.
Another ADME limitation that affects many medicines is the formation of toxic or biologically reactive metabolites.
As a result, some patients receiving the drug may experience toxicities, or the safe dosing of such drugs may be limited, such that patients receive a suboptimal amount of the active agent.
In addition, deuterium analogs, although their size and shape are not significantly altered as compared to the non-deuterated analogs, have increased molecular weight.
This increased molecular weight may affect their ADME profiles in a surprising and unpredictable manner to alter their efficacy in vivo.

Method used

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  • Deuterated tetrapeptides that target mitochondria
  • Deuterated tetrapeptides that target mitochondria
  • Deuterated tetrapeptides that target mitochondria

Examples

Experimental program
Comparison scheme
Effect test

example 1

of Phe-D-Arg-Phe-(3,3,4,4,5,5,6,6-octadeuterium)-Lys-NH2

[0264]

Step 1. Synthesis of (N2-Cbz-N6-Boc-3,3,4,4,5,5,6,6-d8)-Lys-NH2

[0265]

[0266]To a stirring solution of (N2-Cbz-N6-Boc-3,3,4,4,5,5,6,6-d8)-L-Lys-OH (A, 1717 mg, 4.42 mmol) in dry DMF (22 mL) was added carbonyldiimidazole (932 mg, 5.75 mmol) in one portion. The mixture stirred for 1.5 h at rt then aqueous ammonia (0.45 mL, 6.63 mmol, 14.8 M) was added dropwise. After stirring an additional 3 h, no starting material remained (LC / MS). The mixture was concentrated. The resulting residue was partitioned between DCM (130 mL) and sat. NaHCO3 (50 mL). The organic layer was washed with sat. NaHCO3 (2×50 mL), water (50 mL), 5% citric acid (2×50 mL), then brine (50 mL). The organic layer was then dried over anh. Na2SO4, and concentrated to yield product (1599 mg, 93%) as white solid. Used further without additional purification. 1H NMR (300 MHz, CD3OD-d4) δ: 7.43-7.24 (m, 5H), 5.16-5.01 (m, 2H), 4.06 (s, 1H), 1.42 (s, 9H).

Step 2. Synth...

example 2

of Phe-D-Arg-Phe-(4,4,5,5-d4)-Lys-NH2 Trifluoroacetate

[0273]

Step 1. Synthesis of (N2-benzyloxycarboxyl-N6-tert-butoxycarboxyl-4,4,5,5-d4)-Lys-NH2

[0274]

[0275]To a stirring solution of (N2-Cbz-N6-Boc-4,4,5,5-d4)-Lys-OH (F, 384 mg, 1.0 mmol) in dry DMF (5 mL) was added carbonyldiimidazole (162 mg, 1.3 mmol) in one portion. The mixture stirred for 1.5 h at rt then aqueous ammonia (0.10 mL, 1.5 mmol, 14.8 M) was added drop-wise. After stirring an additional 3 h, no starting material remained (LC / MS). The mixture was concentrated. The resulting residue was partitioned between DCM (30 mL) and sat. NaHCO3 (12 mL). The organic layer was washed with sat. NaHCO3 (2×12 mL), water (12 mL), 5% citric acid (2×12 mL), then brine (12 mL). The organic layer was then dried over anh. Na2SO4, and concentrated (TLC, DCM-MeOH (10:1) Rf(PR) 0.5). (N2-Cbz-N6-Boc-4,4,5,5-d4)-Lys-OH (376 mg, 98%), which was used without further purification. 1H NMR (300 MHz, CD3OD-d4) δ: 7.43-7.20 (m, 5H), 5.17-5.00 (m, 2H), ...

example 3

of Phe-D-Arg-Phe-(2,5,5-d3)-Lys-NH2 Trifluoroacetate

[0282]

Step 1: Synthesis of (N6-Boc-2,5,5-d3)-Lys

[0283]

[0284]L-(2,5,5-d3)-Lysine hydrochloride (J, 1.30 mmol, 241 mg) was dissolved in 2 M NaHCO3 (1.30 mL, 2.6 mmol, 218 mg), to which a solution of CuSO4x5H2O (0.65 mmol, 162 mg) in H2O (1.30 mL) was added. An additional NaHCO3 (109 mg, 1.30 mmol) was added, followed by ditertbutyldicarbonate (1.43 mmol, 312 mg) dissolved in 1.6 mL acetone. The mixture stirred 24 h, then methanol (0.50 mL) was added to the solution, and stirring continued 14 h. To the reaction mixture H2O (1 mL) is added and the product was subsequently filtered, washed with H2O (3×1 mL) and dried to give 286 mg (79% yield) of [(N6-Boc-2,5,5-d3)-lysine]2Cu as pale blue solid. To remove the copper, the pale blue Cu-chelate (286 mg, 0.511 mmol) was suspended in H2O (11 mL). Thereafter, 8-quinolinol (200 mg, 1.38 mmol) was added, and the mixture stirred 20 h (pale salad-green precipitate formation). The suspension was f...

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Abstract

Disclosed are deuterated analogs of SBT-20 and elamipretide (MTP-131). The compounds are useful for the treatment and prevention of ischemia-reperfusion injury (e.g., cardiac ischemia-reperfusion injury) or myocardial infarction.

Description

RELATED APPLICATION[0001]This application claims the benefit of priority to U.S. Provisional Patent Application Ser. No. 62 / 586,336, filed Nov. 15, 2017.BACKGROUND OF THE INVENTION[0002]Many current medicines suffer from poor absorption, distribution, metabolism and / or excretion (ADME) properties that prevent their wider use or limit their use in certain indications. Poor ADME properties are also a major reason for the failure of many drug candidates in clinical trials. While formulation technologies and prodrug strategies can be employed in some cases to improve or alter certain ADME properties, these approaches often fail to address the underlying ADME problems that exist for many drugs and drug candidates. One such problem is rapid metabolism that causes a number of drugs, which otherwise would be highly effective in treating a disease, to be cleared too rapidly from the body. A possible solution to rapid drug clearance is frequent or high dosing to attain a sufficiently high pla...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K5/107A61P13/12
CPCC07K5/1016A61K38/00A61P13/12C07K1/02
Inventor ZHENG, GUOZHU
Owner STEALTH BIOTHERAPEUTICS INC
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